The present invention relates to combinations of quinupristine and dalfopristine with cefepime, which combinations can exhibit a synergism of action including bacteriostatic, as well as bactericidal, activity.
The present invention also relates to injectable pharmaceutical compositions intended for parenteral administration, which compositions comprise quinupristine and dalfopristine, in combination with cefepime.
European patent application EP 248,703, the disclosure of which is specifically incorporated by reference herein, describes streptogramin derivatives of group B of general formula: 
as well as their combinations with streptogramin derivatives of group A of the general structure: 
Streptogramin derivatives of group A are described in more detail in European patent no. EP 191,662, the disclosure of which is specifically incorporated by reference herein.
Quinupristine, a derivative of pristinamycin I (a group B streptogramin), and dalfopristine, a derivative of pristinamycin II (a group A streptogramin), are the components of Synercid(copyright): 
Synercid(copyright) (quinupristine/dalfopristine) is an injectable 30/70 combination potent against most gram-positive pathogens, including methicillin resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium (VREF). Its antibacterial activity is cited in many publications, including The Annals of Pharmacotherapy, 29, 1022-1026 (1995); Microbial Drug Resistance, 1, 223-234 (1995); and Antimicrobial Agents Chemother., 39, 1419-1424 (1995); etc.
International patent application WO 98/22107, the disclosure of which is specifically incorporated by reference herein, describes the preparation of stabilized pharmaceutical compositions comprising a quinupristine/dalfopristine combination, achieved in salt form, by adding at least stoichiometric amounts of methanesulphonic acid or of hydrochloric acid, and at a pH within the range of 3.5 to 5.0.
In the clinical environment, some bacteria, MRSA for instance, may jeopardize the efficacy of quinupristine/dalfopristine if adequate concentrations of dalfopristine are not present at the infection site. One way of circumventing this problem has been by increasing the number of doses of quinupristine/dalfopristine within a 24-hr period, or using a system of continuous infusion.
Cefepime is a compound of the class of xcex2-lactams of the cephalosporin related structure: (6R,7R)-7-(2-(2-aminothiazol-4-yl)-2(Z)-(methoxyimino)acetamido)-3-(1-methyl-pyrrolidiniomethyl)-3-cephem-4-carboxylate [Drugs of the Future, 10(10), 805 (1985), the disclosure of which is specifically incorporated by reference herein], which is usually administered by injection in patients with moderate to severe infections.
It has now been found, and this forms the subject of the present invention, that the combination of quinupristine/dalfopristine with cefepime can be of high interest in the treatment of difficult-to-treat or life-threatening infections that require rapid bactericidal activity, as such combination can exhibit a synergy of action against such bacteria. The synergy results in a much higher potency which can, for instance, allow a decrease of the concentration of quinupristine/dalfopristine for administration or widen the dosing interval necessary to inhibit and to kill said bacteria, in particular against multi-drug resistant staphylococci, including methicillin-resistant strains.
Both in vitro and in vivo animal studies have been carried out and results of each confirm the other.
The experimental studies have been carried out in rats with experimental multi-resistant MRSA Endocarditis.